Phenylpyrrole derivatives and their use as antipsychotic agents

ABSTRACT

This invention relates to compounds of formula (I): ##STR1## wherein R 1  represents C 1-4  alkyl; and 
     R 2 , R 3 , R 4  and R 5  each independently represent hydrogen, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  alkoxyC 1-4  alkyl, C 1-4  alkylsulphonyl, trifluoromethylsulphonyl; optionally substituted arylsulphonyl, optionally substituted heteroarylsulphonyl, optionally substituted aralkylsulphonyl, optionally substituted heteroaralkylsulphonyl, nitro, cyano, amino, mono- or di-alkylamino, trifluoromethyl, trifluoromethoxy, hydroxyl, hydroxyC 1-4  alkyl, C 1-4  alkylthio, C 1-4  alkanoyl, C 1-4  alkoxycarbonyl, aminosulphonyl, or mono- or diC 1-4  alkylaminosulphonyl; or 
     R 1  and R 2  together form a linking chain --(CH 2 ) m  Op; (wherein m is 2 to 4 and p is zero or 1) which chain may be optionally substituted by one or two C 1-4  alkyl groups; 
     and Y represents a group of formula (α): ##STR2## wherein each of n and m independently represent an integer from 1 to 3; and salts thereof, having activity at dopamine receptors and potential utility in the treatment of psychoses such as schizophrenia.

This application is a 371 of PCT/EP94/00992 filed on Mar. 29, 1994.

The present invention relates to novel phenylpyrrole derivatives,processes for their preparation, pharmaceutical compositions containingthem and their use in therapy, in particular as and psychotic agents.

European Patent Application No. 241053, describes compounds of theformula: ##STR3## wherein A is an unsaturated 5-membered heterocyclicring, such as 2,5-pyrrolyl, or 3,5- or 1,4- pyrazolyl; X is a nitrogenor carbon atom; R₁, R₂, R₃ are each hydrogen or alkyl; R₄ is aryl,heteroaryl, arylcarbonyl or heteroaryl-carbonyl; R is selected from avariety of substituents and n is 0-4. The compounds are said to haveantipsychotic properties.

European Patent Application No. 259930 describes compounds of theformula: ##STR4## wherein A is an unsaturated 5-membered heterocyclicring, such as 2,5-pyrrolyl, 1,4-pyrazolyl or 2,5-furyl; R is hydrogen,alkyl or optionally substituted phenyl; R¹ is alkyl, alkenyl or forms aring with the phenyl group; R² is hydrogen, hydroxy or alkoxy; R³ isselected from a variety of substituents and n is 0-3. These compoundsare also said to have antipsychotic properties.

We have now found a novel class of 2-phenylpyrroles which exhibitdopamine antagonist activity and thus have potential as antipsychoticagents.

In a first aspect the present invention provides compounds of formula(I): ##STR5## wherein R¹ represents C₁₋₄ alkyl; and

R², R³, R⁴ and R⁵ each independently represent hydrogen, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxyC₁₋₄ alkyl, C₁₋₄ alkylsulphonyl,trifluoromethylsulphonyl; optionally substituted arylsulphonyl,optionally substituted heteroarylsulphonyl, optionally substitutedaralkylsulphonyl, optionally substituted heteroaralkylsulphonyl, nitro,cyano, amino, mono- or di-alkylamino, trifluoromethyl, trifluoromethoxy,hydroxyl, hydroxyC₁₋₄ alkyl, C₁₋₄ alkylthio, C₁₋₄ alkanoyl, C₁₋₄alkoxycarbonyl, aminosulphonyl, or mono- or diC₁₋₄ alkylaminosulphonyl;or

R¹ and R² together form a linking chain --(CH₂)_(m) Op; (wherein m is 2to 4 and p is zero or 1) which chain may be optionally substituted byone or two C₁₋₄ alkyl groups;

and Y represents a group of formula: ##STR6## wherein each of n and mindependently represent an integer from 1 to 3; and salts thereof.

In the compounds of formula (I) an alkyl group or moiety may be straightor branched. Alkyl groups which may be employed include methyl, ethyl,n-propyl, n-butyl, n-pentyl; n-hexyl and any branched isomers thereofsuch as isopropyl, t-butyl, sec-pentyl and the like.

A halogen atom present in the compounds of formula (I) may be afluorine, chlorine, bromine or iodine atom.

When R¹ and R² together form a group --(CH₂)_(m) Op wherein p is 1 itwill be appreciated that the oxygen atom is attached to the phenyl ringat the R² position: ##STR7##

When the (CH₂)_(m) moiety is substituted by two C₁₋₄ alkyl groups theseare preferably substituted on the same carbon atom e.g. a gem-dimethylsubstituent.

Representative aryl groups or moieties present in any of thesubstituents R², R³, R⁴ and R⁵ in compounds of formula (I) includephenyl, naphthyl, and tetrahydronaphthyl. Suitable examples ofheteroaryl groups include both 5 and 6-membered heterocycles containingone or more oxygen, sulphur or nitrogen atoms, such as furyl, thienyl,pyrryl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,pyridyl, pyridazyl, pyrimidyl and pyrazyl. Suitable substituents forsaid aryl and heteroaryl groups include halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ alkoxyC₁₋₄ alkyl, nitro, cyano, amino, mono- or diC₁₋₄alkylamino, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC₁₋₄alkyl, C₁₋₄ alkanoyl and C₁₋₄ alkoxycarbonyl.

R¹ preferably represents methyl or ethyl, or together with R² forms aC₂₋₃ alkylene chain.

Preferably at least one of R² to R⁵ is hydrogen, and the othersubstituents are selected from halogen, C₁₋₂ alkyl, C₁₋₂ alkoxy,phenylsulphonyl, C₁₋₃ alkylsulphonyl, CF₃ and CF₃ O.

In the group Y n is preferably 1 or 2 and m is preferably 1 or 2. Forexample n may be 1 and may be 2 or n and m may both be 1 or n and m mayboth be 2.

It will be appreciated that for use in medicine the salts of formula (I)should be physiologically acceptable. Suitable physiologicallyacceptable salts will be apparent to those skilled in the art andinclude for example acid addition salts formed with inorganic acids eg.hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; andorganic acids eg. succinic, maleic, acetic, fumaric, citric, tartaric,acetic, benzoic, p-toluenesulphonic, methanesulphonic ornaphthalenesulphonic acid. Other non-physiologically acceptable saltsmay be used, for example in the isolation of compounds of formula (I)and are included within the scope of this invention. Also includedwithin the scope of the invention are solvates and hydrates of compoundsof formula (I).

The compounds of formula (I) contain two asymmetric centres andtherefore exist in the form of diastereoisomers. All possiblediastereomeric forms (individual diastereoisomers and mixtures thereof)of compounds of formula (I) are included within the scope of theinvention. The diastereoisomers of compounds of formula (I) includepairs of enantiomers. The present invention includes within its scopeall such enantiomers and mixtures, including racemates.

In particular compounds (I) can exist as pairs of syn and antidiastereoisomers with regard to the relative orientation of the hydrogenatoms shown in the group Y below: ##STR8##

Preferred compounds of the present invention are those compounds offormula (I) contained in the slower eluting pair of diastereoisomers(the antidiastereoisomers) from neutral alumina chromatography.

Particular compounds according to the invention include:

2- 9-(6,9-anti-(1-azabicyclo4.3.0!nonyl))!-5-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole,

2- 2-(2,6-anti-(1-azabicyclo4.4.0!decyl))!-5-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole,

2- 9-(6,9-anti-(1-azabicyclo4.3.0!nonyl))!-5-(5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole,

2- 2-(2,6-anti-(1-azabicyclo4.4.0!decyl))!-5-(3-bromo-5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole,

2- 9-(6,9-anti-(1-azabicyclo4.3.0!nonyl))!-5-(3-bromo-5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole,

2- 9-(6,9-syn-(1-azabicyclo4.3.0!nonyl))!-5-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole,

2- 2-(2,6-syn-(1-azabicyclo4.4.0!decyl))!-5-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole,

2- 9-(6,9-syn-(1-azabicyclo4.3.0!nonyl))!-5-(5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole,

2- 2-(2,6-syn-(1-azabicyclo4.4.0!decyl))!-5-(3-bromo-5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole,

2- 9-(6,9-syn-(1-azabicyclo4.3.0!nonyl))!-5-(3-bromo-5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole,

and salts thereof.

The present invention also provides a process for preparing compounds offormula (I) which process comprises:

carrying out a Vilsmeier reaction with a compound of formula (II):##STR9## and an oxo derivative of the group Y: ##STR10## and reducingthe intermediate product with, for example, sodium borohydride or sodiumcyanoborohydride;

and optionally thereafter forming a salt of formula (I).

The Vilsmeier reaction may be effected according to conventionalmethods. Thus, for example, the oxo derivative of the group Y may firstbe reacted with phosphorus oxychloride (POCl₃) and the resulting productsubsequently reacted with a compound of formula (II) conveniently in asolvent such as dichloromethane. The product of this reaction is thenreduced with, for example, sodium borohydride or cyanoborohydride. Thereduction may be carried out in a suitable solvent, for exampledichloroethane dichloromethane, methanol, ethanol, water or mixturesthereof.

A compound of formula (II) may be prepared by cyclisation of adicarbonyl compound of formula (IV): ##STR11##

The reaction may be effected using an ammonium salt, e.g. ammoniumacetate, in a solvent such as ethanol. (See, for example, C. G. Kruse etal., Heterocycles, vol 26, P3141, 1987).

A compound of formula (IV) may itself be prepared by reacting theappropriate substituted benzoyl halide with a metallo derivative of a2-(2-haloethyl)-1,3-dioxolane or 2-(2-haloethyl)-1,3-dioxane andsubsequent acid hydrolysis.

Compounds of formula (III) which may be employed in the above processinclude 3-indolizidinone and 4-quinolizidinone. Such compounds may beprepared by methods described in the literature (e.g. Chem. Abs., 1964,60, 1691f and Chem. Abs., 1963, 59, 3889d).

When a compound of formula (I) is obtained as a mixture of enantiomersthese may be separated by conventional methods such as crystallisationin the presence of a resolving agent, or chromatography, for exampleusing a chiral HPLC column.

Compounds of formula (I) have been found to exhibit affinity fordopamine receptors, in particular D₃ receptors, and are expected to beuseful in the treatment of disease states which require modulation ofsuch receptors, such as psychotic conditions. The therapeutic effect ofcurrently available antipsychotic agents (neuroleptics) is generallybelieved to be exceed via blockade of D₂ receptors; however thismechanism is also thought to be responsible for undesirableextrapyramidal side effects (eps) associated with many neurolepticagents. Without wishing to be bound by theory, it has been suggestedthat blockade of the recently characterised dopamine D₃ receptor maygive rise to beneficial antipsychotic activity without significant eps.(see for example Sokoloff et al, Nature, 1990; 347: 146-151; andSchwartz et al, Clinical Neuropharmacology, Vol 16, No. 4, 295-314,1993). Preferred compounds of the present invention are therefore thosewhich have higher affinity for dopamine D₃ than dopamine D₂ receptors(such affinity can be measured using standard methodology for exampleusing cloned dopamine receptors). Said compounds may advantageously beused as selective modulators of D₃ receptors. In particular compounds offormula (I) are dopamine D₃ receptor antagonists and as such are ofpotential use as antipsychotic agents for example in the treatment ofschizophrenia, schizo-affective disorders, psychotic depression andmania. Other conditions which may be treated by modulation of dopamineD₃ receptors include dyskinetic disorders such as Parkinson's disease,neuroleptic-induced parkinsonism and tardive dyskinesias; depression;and drug (eg. cocaine) dependency.

In a further aspect therefore the present invention provides a method oftreating conditions which require modulation of dopamine D₃ receptors,for example psychoses such as schizophrenia, which comprisesadministering to a subject in need thereof an effective amount of acompound of formula (I) or a physiologically acceptable salt thereof.

The invention also provides the use of a compound of formula (I) or aphysiologically acceptable salt thereof in the manufacture of amedicament for the treatment of conditions which require modulation ofdopamine D₃ receptors, for example psychoses such as schizophrenia.

For use in medicine, the compounds of the present invention are usuallyadministered as a standard pharmaceutical composition. The presentinvention therefore provides in a further aspect pharmaceuticalcompositions comprising a novel compound of formula (I) or aphysiologically acceptable salt thereof and a physiologically acceptablecarrier.

The compounds of formula (I) may be administered by any convenientmethod, for example by oral, parenteral, buccal, sublingual, nasal,rectal or transdermal administration and the pharmaceutical compositionsadapted accordingly.

The compounds of formula (I) and their physiologically acceptable saltswhich are active when given orally can be formulated as liquids orsolids, for example syrups, suspensions or emulsions, tablets, capsulesand lozenges.

A liquid formulation will generally consist of a suspension or solutionof the compound or physiologically acceptable salt in a suitable liquidcarrier(s) for example an aqueous solvent such as water, ethanol orglycerine, or a non-aqueous solvent, such as polyethylene glycol or anoil. The formulation may also contain a suspending agent, preservative,flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example, pellets containing the activeingredient can be prepared using standard carriers and then filled intoa hard gelatin capsule; alternatively, a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), for exampleaqueous gums, celluloses, silicates or oils and the dispersion orsuspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound or physiologically acceptable salt in a sterile aqueouscarrier or parenterally acceptable oil, for example polyethylene glycol,polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.Alternatively, the solution can be lyophilised and then reconstitutedwith a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active substance in aphysiologically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal once the contents of the container have been exhausted. Wherethe dosage form comprises an aerosol dispenser, it will contain apropellant which can be a compressed gas such as compressed air or anorganic propellant such as a fluorochlorohydrocarbon. The aerosol dosageforms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles, wherein the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal administration are conveniently in the form ofsuppositories containing a conventional suppository base such as cocoabutter.

Compositions suitable for transdermal administration include ointments,gels and patches.

Preferably the composition is in unit dose form such as a tablet,capsule or ampoule.

Each dosage unit for oral administration contains preferably from 1 to250 mg (and for parenteral administration contains preferably from 0.1to 25 mg) of a compound of the formula (I) or a physiologicallyacceptable salt thereof calculated as the free base.

The physiologically acceptable compounds of the invention will normallybe administered in a daily dosage regimen (for an adult patient) of, forexample, an oral dose of between 1 mg and 500 mg, preferably between 10mg and 400 mg, e.g. between 10 and 250 mg or an intravenous,subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg,preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of thecompound of the formula (I) or a physiologically acceptable salt thereofcalculated as the free base, the compound being administered 1 to 4times per day. Suitably the compounds will be administered for a periodof continuous therapy, for example for a week or more.

The invention is further illustrated by the following non-limitingexamples:

EXAMPLE 1

2- 9-(1-Azabicyclo4.3.0!nonyl)!-5-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole hydrochloride(6,9-syn- and 6,9-anti- isomers)

Phosphorus oxychloride (0.25 ml, 2.7 mmol) was added to 3-indolizidinone(0.34 g, 2.4 mmol) Chem. Abstr., 1964, 60, 1691f! at room temperatureunder argon with constant stirring. The resulting viscous oil wasstirred at 40° C. for 16 hours and then 1,2-dichloroethane (2 ml) wasadded. The reaction mixture was cooled to 0° C., then a solution of2-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole (0.405 g, 1.2 mmol) in1,2-dichloroethane (4 ml) was added dropwise. The reaction mixture wasstirred at 0° to 5° C. for 2 hours, then at room temperature for 18hours. Sodium borohydride (0.418 g, 11.1 mmol) was added portionwisewith ice cooling and stirring at room temperature was carried out for 3hours. The mixture was cooled to 0° C. and treated dropwise with water(2 ml) followed by methanol (2 ml). When effervescence had subsided, themixture was poured onto water (30 ml) and extracted with dichloromethane(3×30 ml). The combined organic extracts were dried over anhydroussodium sulphate, then evaporated in vacuo to give an oil. The boranecomplex was treated With a mixture of hydrochloric acid (35%; 2.0 ml)and methanol (4.0 ml) and the resulting solution stirred for 18 hours.The solution was treated with water (20 ml) and aqueous sodium hydroxide(40%; 2.55 ml) then extracted with dichloromethane (3×30 ml). Thecombined extracts were dried over anhydrous sodium sulphate andevaporated in vacuo to give an oil (0.70 g). Chromatography on alumina(Brockmann grade 1) with ether (30-100%)--pentane gradient elutionfollowed by ether-methanol (0-1%) gradient elution gave the free base ofthe title compound as two pairs of diastereoisomers. Faster eluting pairA (0.135 g) and slower eluting pair B (0.186 g) were isolated ascolourless oils. Faster eluting pair A (0.122 g) was dissolved in ether,and the solution washed with water (3×20 ml), then extracted withhydrochloric acid (0.1M; 3×30 ml). The combined aqueous extracts wereextracted with dichloromethane (3×30 ml), and the combined organicextracts were dried over anhydrous sodium sulphate and evaporated invacuo to give the title compound (faster eluting pair ofdiastereoisomers A) as a white foam (0.129 g, 22%). The hydrochloridesalt of the slower eluting pair of diastereoisomers B (0.114 g; 19% )was prepared in an analogous manner from the free base (0.175 g), andobtained as a white foam.

Faster Eluting Pair of Diastereoisomers A -Syn (Free Base)

NMR δ (200 MHz; CDCl₃) 1.18-1.32 (2H,m), 1.40-1.69 (4H,br m), 1.73-1.93(4H, br m), 1.95-2.15 (2H,br m), 2.81-2.94 (1H,br m), 3.25-3.40 (1H, brm), 3.73 (3H, s), 6.09 (1H,br s), 6.48 (1H,br s), 7.46 (1H,d), 7.63(1H,br s) and 9.71 (1H,br s).

Slower Eluting Pair of Diastereoisomers B -Anti (Free Base)

NMR δ (200 MHz; CDCl₃) 1.15-1.36 (2H,m), 1.40-1.63 (3H,m), 1.66-1.95(3H,m), 2.02-2.21 (2H,m), 2.28-2.47 (1H,m), 2.61-2.78 (1H,m), 2.82-2.92(1H,m), 3.73 (3H,s), 4.26-4.34 (1H,m), 6.06 (1H,t), 6.52 (1H,t), 7.47(1H,d), 7.63 (1H,d) and 9.62 (1H,br s).

EXAMPLE 2

2- 2-(1-Azabicyclo4.4.0!decyl)!-5-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole hydrochloride(2,6-syn- and 2,6-anti- isomers)

Phosphorus oxychloride (0.17 ml, 1.82 mmol) was added to4-quinolizidinone (0.28 g, 1.83 mmol) Chem. Abstr., 1963, 59, 3889d! atroom temperature under argon with constant stirring. The resultingviscous oil was stirred at 40° C. for 2 hours and then1,2-dichloroethane (1.4 ml) was added. The reaction mixture was cooledto 0° C., then a solution of 2-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole(0.406 g, 1.23 mmol) in 1,2-dichloroethane (4 ml) was added dropwise.The reaction mixture was allowed to warm to room temperature and wasstirred for 18 hours at 20° C. and then for 3 hours at 70°-80° C. Sodiumborohydride (0.423 g, 11.0 mmol) was added portionwise with ice cooling,and stirring at room temperature was carried out for 3 hours. Themixture was cooled to 0° C. and treated dropwise with water (2 ml)followed by methanol (2 ml). When effervescence had subsided, themixture was poured onto water (30 ml) and extracted with dichloromethane(3×30 ml). The combined organic extracts were dried over anhydroussodium sulphate, then evaporated in vacuo to give an oil. The boranecomplex was treated with a mixture of hydrochloric acid (35%; 2 ml) andmethanol (4 ml) and the resulting solution stirred for 18 hours at roomtemperature. The solution was treated with water (20 ml) and aqueoussodium hydroxide (40%; 2.6 ml) then extracted with dichloromethane (3×30ml). The combined extracts were dried over anhydrous sodium sulphate andevaporated in vacuo to give an oil (0.70 g). Chromatography on alumina(Brockmann grade 1) with ethyl acetate (10-100%)--pentane gradientelution followed by ethyl acetate--methanol (0-1% ) gradient elutiongave the free base of the title compound as two pairs ofdiastereoisomers. Faster eluting pair A (0.378 g) and slower elutingpair B (0.063 g) were isolated as yellow oils. Faster eluting pair A(0.43 g) was dissolved in diethyl ether, and the solution was washedwith water (3×20 ml), then extracted with hydrochloric acid (0.1M; 3×30ml). The combined aqueous extracts were extracted with dichloromethane(3×30 ml), and the combined organic extracts were dried over anhydroussodium sulphate and evaporated in vacuo to give the title compound(faster eluting pair of diastereoisomers A) as a white foam (0.37 g,60%). The hydrochloride salt of the slower eluting pair ofdiastereoisomers B was prepared in an analogous manner from the freebase (0.063 g) and was obtained as a white foam (0.036 g, 6%).

Faster Eluting Pair Of Diastereoisomers A -Syn (Hydrochloride Salt)

NMR δ (400 MHz; CDCl₃) 1.40-1.52 (1H,m), 1.60-1.81 (2H,m), 1.81-1.96(3H,m), 1.99-2.23 (4H,m), 2.28-2.43 (2H,m), 2.80-2.93 (2H,m), 3.22-3.30(1H,m), 3.80 (3H,s), 3.76-3.85 (1H,m), 6.20 (1H,t), 6.66 (1H,t), 7.51(1H,d), 7.94 (1H,d), 11.57 (1H,br s) and 11.94 (1H,br s).

Slower Eluting Pair Of Diastereoisomers B -Anti (Hydrochloride Salt)

NMR δ (400 MHz; CDCl₃) 1.51-1.95 (6H,m), 1.96-2.39 (4H,m), 2.61-2.84(2H,m), 2.85-2.89 (1H,m), 3.00-3.19 (1H,m), 3.64-3.75 (1H,m), 3.78(3H,s), 4.42-4.53 and 5.09-5.18 (1H, 2x m), 6.24, 6.45, 6.66 and 6.71(2H,4x br s), 7.52 (1H,br s), 7.90 (1H,br s), 10.83 and 12.30 (1H, 2x brs) and 11.39 (1H,br s).

EXAMPLE 3

2- 9-(1-Azabicyclo4.3.0!nonyl)!-5-(5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrolehydrochloride (6,9-syn- and 6,9-anti- isomers)

The title compound was prepared by a method analogous to that used toprepare example 1, but using2-(5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole in place of2-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole.

Faster fluting pair of diastereoisomers A -Syn (hydrochloride salt)

NMR δ (CDCl₃) 1.28 (3H, t, J=7 Hz), 1.45 (1H, m), 1.76 (2H, m), 2.04(2H, m), 2.22 (2H, m), 2.43 (3H, m), 2.69 (1H, m), 2.95 (1H, m), 3.20(2H, q, J=7 Hz), 3.42 (1H), m), 3.98 (1H, q, J=10 Hz), 4.15 and 4.22(3H, 2x s), 6.28 and 6.32 (1H, 2x t, J=3 Hz), 6.60 and 6.64 (1H, 2x t,J=3 Hz), 7.07 and 7.09 (1H, 2x d, J=9 Hz), 7.7 (1H, dd, J=9 Hz and 2Hz), 8.12 and 8.15 (1H, 2x d, J=2 Hz), 11.34 and 11.70 (1H, 2x br.s) and12.00 and 12.23 (1H, 2x br.s).

Mass spectrum: Found M⁺ 388.1826; C₂₁ H₂₈ N₂ O₃ S requires 388.1821

Slower fluting pair of diastereoisomers B -Anti (hydrochloride salt)

NMR δ (CDCl₃) 1.28 (3H, t, J=7 Hz), 1.30-2.50 (8H, m), 2.69 (2H, m),3.09 (1H, m), 3.17 (2H, q, J=7 Hz), 3.45 (1H, m), 3.90 (1H, br.s), 4.17(3H,m), 4.57 and 5.35 (1H, 2x br.s), 6.31 (1H, t, J=3 Hz), 6.62 and 6.72(1H, 2x m), 7.09 (1H, d, J=9 Hz), 7.72 (1H, d, J=9 Hz), 8.14 (1H, s),10.58 and 12.42 (1H, 2x br.s) and 11.40 (1H, br.s).

Mass spectrum: Found M⁺ 388.1827; C₂₁ H₂₈ N₂ O₃ S requires 388.1821

EXAMPLE 4

2- 2-(1-Azabicyclo4.4.0!decyl)!-5-(3-bromo-5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrolehydrochloride (2,6-syn- and 2,6-anti- isomers)

The title compound was prepared by a method analogous to that used toprepare example 2, but using2-(3-bromo-5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole in place of2-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole. It was necessary, however,to perform the Vilsmeier reaction at 100° C. instead of at roomtemperature, in order to effect total conversion to the desiredproducts.

Faster eluting pair of diastereoisomers A -Syn (hydrochloride salt)

NMR δ (CDCl₃) 1.35 (3H, t, J=7 Hz), 1.46 (1H, m), 1.72 (3H, m), 1.90(2H, m), 2.08 (4H, m), 2.35 (2H, m), 2.85 (2H, m), 3.26 (1H, d), 3.41(2H, q, J=7 Hz), 3.81 (1H, m), 3.86 (3H, s), 6.22 (1H, t, J=3 Hz), 6.70(1H, t, J=3 Hz), 7.96 (1H, d, J=2 Hz), 8.26 (1H, d, J=2 Hz), 11.62 (1H,br.s) and 11.88 (1H, br.s).

Mass spectrum: Found M⁺ 480.1055; C₂₂ H₂₉ BrN₂ O₃ S requires 480.1082

Slower eluting pair of diastereoisomers B -Anti (hydrochloride salt)

NMR δ (CDCl₃) 1.34 (3H, t, J=7 Hz), 1.62 (7H, m), 1.88 (1H, m), 2.00(1H, m), 2.12 (1H, m), 2.70 (2H, m), 2.94 (1H, m), 3.05 (1H, m), 3.37(2H, q, J=7 Hz), 3.70 (1H, m), 3.86 (3H, s), 4.50 (1H, m), 6.26 (1H,br.s), 6.70 (1H, br.s), 7.96 (1H, d, J=2 Hz), 8.22 (1H, d, J=2 Hz),11.69 (1H, br.s) and 12.09 (1H, br.s).

Mass spectrum: Found M⁺ 480.1087; C₂₂ H₂₉ BrN₂ O₃ S requires 480.1082

EXAMPLE 5

2- 9-(1-Azabicyclo4.3.0!nonyl)!-5-(3-bromo-5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrolehydrochloride (6,9-syn- and 6,9-anti- isomers)

The title compound was prepared by a method analogous to that used toprepare example 1, but using2-(3-bromo-5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole in place of2-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole. As for example 4, it wasnecessary to perform the Vilsmeier reaction at 100° C.

Faster during pair of diastereoisomers A -Syn (hydrochloride salt)

NMR δ (CDCl₃) 1.34 (3H, t, J=7 Hz), 1.46 (1H, m), 1.86 (1H, m), 2.10(3H, m), 2.32 (2H, m), 2.45 (3H, m), 2.62 (1H, m), 2.98 (1H, m), 3.41(3H, overlapping m and q, J=7 Hz), 3.85 (3H, s), 4.03 (1H, m), 6.30 (1H,t, J=3 Hz), 6.72 (1H, t, J=3 Hz), 7.97 (1H, d, J=2 Hz), 8.29 (1H, d, J=2Hz), 11.59 (1H, br.s) and 12.02 (1H, br.s).

Mass spectrum: Found M⁺ 466.0909; C₂₁ H₂₇ BrN₂ O₃ S requires 466.0926

Slower eluting pair of diastereoisomers B -Anti (hydrochloride salt)

NMR δ (CDCl₃) 1.32 (3H, t, J=7 Hz), 1.50-3.28 (13H, br.m), 3.36 (2H, q,J=7 Hz), 3.85 (3H, s), 4.63 and 5.49 (1H, 2x br.s), 6.31 (1H, br.s),6.79 (1H, br.s), 7.95 (1H, d, J=2 Hz), 8.26 (1H, br.s), 11.62 (1H, br.s)and 12.15 (1H, br.s).

Mass spectrum: Found M⁺ 466.0967; C₂₁ H₂₇ BrN₂ O₃ S requires 466.0926

DATA

The ability of the compounds to bind selectively to human D₃ dopaminereceptors can be demonstrated by measuring their binding to clonedreceptors. The inhibition constants (IC₅₀) of test compounds fordisplacement of ¹²⁵ I! iodosulpride binding to D₃ dopamine receptorsexpressed in CHO cells have been determined. The cell lines were shownto be free from bacterial, fungal and mycoplasmal contaminants, andstocks of each were stored frozen in liquid nitrogen. Cultures weregrown as monolayers or in suspension in standard cell culture media.Cells were recovered by scraping (from monolayers) or by centrifugation(from suspension cultures), and were washed two or three times bysuspension in phosphate buffered saline followed by collection bycentrifugation. Cell pellets were stored frozen at -40° C. Crude cellmembranes were prepared by homogenisation followed by high-speedcentrifugation, and characterisation of cloned receptors achieved byradioligand binding.

Preparation of CHO cell membranes

Cell pellets were gently thawed at room temperature, and resuspended inabout 20 volumes of ice-cold 50 mM Tris salts (pH 7.4@37° C.), 20 mmEDTA, 0.2M sucrose. The suspension was homogenised using an Ultra-Turraxat full speed for 15 sec. The homogenate was centrifuged at 18,000 r.p.mfor 20 min at 4° C. in a Sorvall RC5C centrifuge. The membrane pelletwas resuspended in ice-cold 50 mM Tris salts (pH 7.4@37° C.), using anUltra-Turrax, and recentrifuged at 18,000 r.p.m for 15 min at 4° C. in aSorvall RC5C. The membranes were washed two more times with ice-cold 50mM Tris salts (pH 7.4@37° C.). The final pellet was resuspended in 50 mMTris salts (pH 7.4@37° C.), and the protein content determined usingbovine serum albumin as a standard (Bradford, M. M. (1976) Anal.Biochem. 72, 248-254).

Binding experiments on cloned dopamine receptors

Crude cell membranes were incubated with 0.1 nM ¹²⁵ I! iodosulpride(˜2000 Ci/mmol; Amersham, U. K.), in a buffer containing 50 mM Trissalts (pH 7.4@37° C.), 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂,0.1% (w/v) bovine serum albumin, in a total volume of 1 ml for 30 min at37° C. Following incubation, samples were filtered using a Brandel CellHarvester, and washed three times with ice-cold 50 mM Tris salts (pH7.4@37° C.), 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂. Theradioactivity on the filters was measured using a Cobra gamma counter(Canberra Packard). Non-specific binding was defined as the radioligandbinding remaining after incubation in the presence of 100 μMiodosulpride. For competition curves, 14 concentrations (half-logdilutions) of competing cold drug were used.

Competition curves were analysed simultaneously whenever possible usingnon-linear least-squares fitting procedures, capable of fitting one, twoor three site models.

Results

The anti- diastereoisomers of Examples 1-5 had IC₅₀ values in the range10.0-50.0 nM, at the D₃ receptor.

We claim:
 1. A compound of formula (I): ##STR12## wherein R₁ representsC₁₋₄ alkyl; andR², R³, R⁴ and R⁵ each independently represent hydrogen,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxyC₁₋₄ alkyl, C₁₋₄alkylsulphonyl, trifluoromethylsulphonyl; optionally substitutedarylsulphonyl, optionally substituted heteroarylsulphonyl, optionallysubstituted aralkylsulphonyl, optionally substitutedheteroaralkylsulphonyl, nitro, cyano, amino, mono- or di-alkylamino,trifluoromethyl, trifluoromethoxy, hydroxyl, hydroxyC₁₋₄ alkyl, C₁₋₄alkylthio, C₁₋₄ alkanoyl, C₁₋₄ alkoxycarbonyl, aminosulphonyl, or mono-or diC₁₋₄ alkylaminosulphonyl; or R¹ and R² together form a linkingchain --(CH₂)_(m) Op; (wherein m is 2 to 4 and p is zero or 1) whichchain may be optionally substituted by one or two C₁₋₄ alkyl groups;andY represents a group of formula: ##STR13## wherein each of n and mindependently represent an integer from 1 to 3; and salts thereof.
 2. Acompound according to claim 1 wherein R¹ represents methyl or ethyl, ortogether with R² forms a C₂₋₃ alkylene chain.
 3. A compound according toclaim 1 wherein at least one of R² to R⁵ is hydrogen, and the othersubstituents are selected from halogen, C₁₋₂ alkyl, C₁₋₂ alkoxy,phenylsulphonyl, C₁₋₃ alkylsulphonyl, CF₃ and CF₃ O.
 4. A compoundaccording to claim 1 wherein each of n and m in the group Yindependently represent 1 or
 2. 5. A compound according to claim 1selected from:2- 9-(6,9-anti-(1-azabicyclo4.3.0!nonyl))!-5-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole, 2-2-(2,6-anti-(1-azabicyclo4.4.0!decyl))!-5-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole, 2-9-(6,9-anti-(1-azabicyclo4.3.0!nonyl))!-5-(5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole, 2-2-(2,6-anti-(1-azabicyclo4.4.0!decyl))!-5-(3-bromo-5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole,2- 9-(6,9-anti-(1-azabicyclo4.3.0!nonyl))!-5-(3-bromo-5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole,2- 9-(6,9-syn-(1-azabicyclo4.3.0!nonyl))!-5-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole, 2-2-(2,6-syn-(1-azabicyclo4.4.0!decyl))!-5-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole, 2-9-(6,9-syn-(1-azabicyclo4.3.0!nonyl))!-5-(5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole, 2-2-(2,6-syn-(1-azabicyclo4.4.0!decyl))!-5-(3-bromo-5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole,2- 9-(6,9-syn-(1-azabicyclo4.3.0!nonyl))!-5-(3-bromo-5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole,or a salt thereof.
 6. A method of treating a condition which requiresmodulation of a dopamine receptor which comprises administering to asubject in need thereof an effective amount of a compound of formula (I)according to claim 1 or a physiologically acceptable salt thereof.
 7. Apharmaceutical composition comprising a compound of formula (I)according to claim 1 or a physiologically acceptable salt thereof and aphysiologically acceptable carrier.